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The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic

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DOI: 10.22259/2639-1848.0202001

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Archives of Immunology and Allergy
ISSN: 2639-1848
Volume 2, Issue 2, 2019, PP: 01-09

The Interplay between MiRNAs and LncRNAs in the

Pathogenesis of Asthmatic Diseases
Glady Gilbert
President of European Bio Immune(G)ene Medicine Association (EBMA), Colmar, France.
info@ebma-europe.com
*Corresponding Author: Dr. Glady Gilbert, President of European Bio Immune(G)ene Medicine Association
(EBMA), Colmar, France.

Abstract
Asthma affects people of all ethnicities and ages and there has been a substantial increase in the prevalence
of asthma over the past few decades, with current estimates of approximately 300 million people suffering
from the disease worldwide. The initial response consists primarily of airway smooth muscle constriction and
airway inflammation (oedema, inflammatory cell infiltration, increased airway secretions). Whereas more
chronic responses such as structural remodelling of the airway including smooth muscle and sub-mucosal
gland hyperplasia and hypertrophy, extracellular matrix (ECM) deposition and angiogenesis are generally
thought to occur in parallel with inflammatory responses. Asthma is commonly associated with a Th2 response
with infiltration of eosinophils, mast cells and Th2 lymphocytes into the airways, as well as elevated serum
immunoglobulin IgE levels,and is determined by interaction of multiple genes and environmental factors.
MicroRNAs (miRNAs) are small non-coding RNAs of 18–25 nucleotides, that have been shown to regulate
gene expression at the translational level via the RNA interference pathway. In most circumstances, miRNAs
are believed to either repress mRNA translation or induce the degradation of target mRNA. Since asthma
is characterised by chronic inflammation of the airways, it is likely that miRNAs might be important in the
pathogenesis of the disease through modulation of immune cells. Long non-coding RNAs are a heterogeneous
group of non-coding RNAs with regard to origin and mechanism of action/function. Another interesting feature
is that they may be expressed in both sense and antisense orientation relative to protein-coding genes. Studies
demonstrated that they are regulators of different cellular processes including chromatin structure changes,
transcription and post-transcriptional processing, and intracellular trafficking. The interplay between these two
different types of ncRNAs is only starting to be known but appears to be very promising for a better knowledge
of the asthma pathogenesis, and therefore is becoming an exciting challenge in a therapeutic perspective; this
challenge will be faced by the BI(G)MED via the use of ultra-low doses of these molecules of ncRNAs in the
treatment of the asthmatic disease.

Keywords: nc RNAs, microRNAs, lnc RNAs, TH2-regulation, asthma therapy.

Introduction is getting worse. The prevalence of asthma in

The incidence of allergic diseases in general
and asthma in particular is growing in so-called
industrialized countries, raising costs support
higher and higher as well as a co-morbidity that
different countries varies widely, but the disparity
is narrowing due to rising prevalence in low and
middle-income countries and plateauing in high
income countries.

Archives of Immunology and Allergy V2 . I2 . 2019 1

The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases

Fig 1. Asthma Prevalence, World Health Organization Morbidity Database, 2013

As estimated 300 million people worldwide suffer
from asthma, with 250,000 annual deaths attributed to
the disease. It is estimated that the number of people
with asthma will grow by more than 100 million by
2025. About 70% of asthmatics also have allergies, but
occupational asthma contributes significantly to the
global burden of asthma, since the condition accounts
for approximately 15% of asthma amongst adults.
The prognosis of a patient with asthma currently
remains dark at medium to long term, suggesting
that at present there is no appropriate therapy
for stabilization or recovery of chronic asthmatic
condition. A possible reason for this situation is the lack
of a global treatment of the asthmatic disease trying
to regulate all the pathophysiological mechanisms
and comorbidities involved in the development of this
bronchio-pulmonary pathology.
Although it still cannot be cured, control of asthma
may be achieved in the majority of patients with
appropriate education, environmental control,
avoidance of triggers and inducers, and individualized
pharmacotherapy.(1)

Fig 2. Adapted from: Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J. 2009; 33; GERD:
gastro-esophageal reflux disease; OSA: obstructive sleep apnea; COPD: chronic obstructive pulmonary disease
2 Archives of Immunology and Allergy V2 . I2 . 2019
The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases
The following figure, which shows the general somehow traces the contours of a diagnostic and
pathophysiology of allergic disease and asthma, therapeutic approach of holistic type.

Fig 3. General pathophysiology of allergic disease and asthma

“Systems biology” also named “Integrative biology” is a
recent and evolving interdisciplinary field that focuses
on the systematic study of complex interactions in
biological systems.(2)It employs a holistic approach to
study all components and interactions in the network of
DNA (genes), RNA, proteins and biochemical reactions
within a cell or an organism. Several international
consortia have already applied systems biology and
network medicine approaches to asthma research;
ADEPT (Airways Disease Endotyping for Personalised
Therapeutics) and U-BIOPRED (Unbiased Biomarkers
for the Prediction of Respiratory Disease Outcome
Consortium) have, for instance, applied a clustering
algorithm to two independent asthma cohorts on a
small set of easily measurable clinical variables and
successfully defined four longitudinally stable clusters
of patients with distinct clinical and biomarker profiles
(from blood, sputum and airway data).(3)(4)(5)
The term “P4 medicine” (Personalized, Predictive,
Preventive and Participatory medicine) was coined
by David Galas and Leroy Hood from the Institute for
Systems Biology (ISB) in Seattle.

Fig 4. P4 Medicine, Image Courtesy Providence St. Joseph Health

Archives of Immunology and Allergy V2 . I2 . 2019 3
The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases
Two American authors(6) have applied this Two other authors have recently described a precision
concept, although innovative but of incontestable medicine approach that stratifies patients based on
rationality, to allergic diseases in general and disease mechanisms to optimize management of
asthma in particular. We will follow it with a allergic diseases(7). So are evoked diverse phenotypes,
special focus on epigenomic regulation using endotypes, genotypes, regiotypes, and theratypes of
non-coding RNAs. allergic diseases, in particular asthma.
Materials and Methods
Asthma and the Epigenome

Fig 5. Major components of epigenetic regulation in eukaryotes, Nubia AndreaVillota-Salazar & al, Journal
Frontiers in Life Science Volume 9, 2016 - Issue 4
Epigenetic mechanisms control expression levels of long intergenic noncoding RNAs (lncRNAs) are more
genes without changing DNA sequence(8). and more viewed as a part of the epigenome as they
Non-coding RNAs such as micro RNAs (miRNAs) and are involved in regulation of gene expression. (9)

Fig 6. Human genome organization: coding vs. non-coding transcripts

4 Archives of Immunology and Allergy V2 . I2 . 2019
The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases

Asthma and MicroRNAs targeting transcription factors.

MiRNAs are single-stranded RNA molecules of 19-25
nucleotides in length that mediate post-transcriptional
gene silencing of target genes and are highly conserved
throughout evolution. A single miRNA can target
hundreds of genes, and individual genes are typically
targeted by multiple miRNAs, adding complexity to the
network. MiRNAs can also exert global effects on gene
expression by either affecting epigenetic mechanisms,
such as DNA methylation or histone acetylation, or
One approach to identify miRNAs involved in the
pathogenesis of allergy is to uncover miRNAs that are
differentially expressed in normal and affected tissue.
Single nucleotide polymorphisms in both miRNAs
and miRNA target sites have been specifically linked
to asthma. But some years ago,several studies have
already begun to shed light on the role that some
miRNAs play in the development of allergic airway
disease in animal models(10)(11).

Fig 7. Mechanisms of miRNA action involved in severe asthma pathogenesis. Maneechotesuwan K. Respir
Investig. 2019 Jan;57(1)
On a cellular level, type 2 immune responses are T regulatory (Treg) cells, and IgE-producing B cells.
associated with atopic diseases, such as allergy and Critical molecular factors include the production of IgE
asthma. Airway type 2 immune responses are mainly and cytokines such as thymic stromal lymphopoietin
mediated by eosinophils, mast cells, basophils, TH2 (TSLP), interleukin (IL)-25, IL-33, IL-4, IL-13, IL-5 and
cells, group 2 innate lymphoid cells (ILC2s), Th9 cells, IL-9(12).

Fig 8. overview of a type 2‐driven asthma response, Robinson D. & al, Clin Exp Allergy. 2017 Feb; 47(2)
Archives of Immunology and Allergy V2 . I2 . 2019 5
The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases
On the basis of all these data, microRNAs will act at - a role of miRNAs in survival, production, and
different levels of regulation, and we may observe: proliferation of type 2 immune cells(14)
- an expression miRNA profiling in allergic
inflammation(13) - and in M2 polarization as well (15)

Fig 9. regulation of the adaptive immune system by miR-21 in allergic inflammatory responses, Liu F & al, Mol
Med Rep. 2012 Nov;6(5)

Fig 9. miRNAs multifaceted regulation of type 2 cell function; Pua HH, Ansel KM. Curr Opin Immunol. 2015 Oct;36
Studies in multiple cell types, diseases and allergic responses, often through the
model systems have shown that individual modulation of key signaling pathways in type 2
miRNAs can positively or negatively regulate effector responses.

6 Archives of Immunology and Allergy V2 . I2 . 2019

The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases
Asthma and Long Non-Coding RNAs to have functional roles in a diverse range of cellular
LncRNAs are non-coding RNAs that are more than functions such as development, differentiation, cell
200 nucleotides in length. They have been identified fate, as well as disease pathogenesis(16).

Fig 10. General mechanisms for lncRNA classification. Balas MM & Johnson AM. Noncoding RNA Res. 2018 Mar 31;3(3)
LncRNAs are involved in the development of multiple this subject.Thus, for example, the M PERRY group
diseases, including asthma(17) through transcriptional in London, was able to demonstrate the regulatory
or post-transcriptional regulation of protein action of the asthmatic phenotype of long noncoding
expression through various mechanisms. Unlike RNA Plasmocytoma Variant Translocation 1 (lnc
cancer, where studies abound, research about lncRNAs PVT1), which is only increased in the primary Airway
did not pay much attention to the relationship Smooth Muscle Cells (ASMCs) of patients with severe
between these large noncoding RNAs and asthma. asthma, where it decreases IL-6 production and cell
There are nevertheless some interesting works on proliferation (18).

Fig 11. Potential mechanisms for PVT1 contribution to ASMC proliferation and IL-6 release in asthmatic
patients.M M Perry & al, J Allergy Clin Immunol. 2017 Mar; 139(3)
Archives of Immunology and Allergy V2 . I2 . 2019 7
The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic Diseases
Another group was able recently to highlight a similar
role of lnc GAS5 by demonstrating the important role
played by the long noncoding RNA Growth Arrest-
Specific transcript 5 (lncRNA GAS5) / miR-10a / BDNF
regulatory axis in promoting ASMCs proliferation,
thus contributing to asthma.(19)Youngest studies show
that lncRNAs are involved in different phenotypes of
asthma, and especially lnc_000127 may be effective
for reducing Th2 inflammation in Eos asthma.(17)
As the conductor controls the elements of musical
expression (tempo, dynamics, articulation) so finally
lncRNAs orchestrate and modulate gene expression
and cellular functions.
Discussion
A group of clinical physicians and myself conducted a
six-months study published in 2018 (20), which showed
the positive regulatory effect allowing a partial or
complete replacement of a prolonged corticotherapy
in asthma by an immunogenetic nanotherapy.
The general principle is to use for therapeutic purposes
the largest possible number of microRNAs and
lncRNAs, whose involvement in the pathophysiology
of asthma has been validated through the research.
In order to comply with the principle of biomimetics,
we use nanodoses located between nanograms and
femtograms or even lower, whose action will be
driven according to the general principle of Hormesis,
that corresponds to the so-called “dose-response
concept”, which represents the biological integration
of how living systems at all levels of organization,
from the cell to the individual, respond, adapt or fail
to adapt to endogenous agents, metabolic processes,
and externally imposed stressors/threats.(21)
At present, the referenced nanotransporter is xylitol,
but we are developing a more efficient lipid carrier in
a near future.
The results of our study showed that after six months
nearly two-thirds of the patients were able to reduce
significantly or stop definitively their previous
corticotherapy.
Conclusion
In asthma
• miRNAs regulate allergic inflammation.
• miRNAs act coordinately through target gene
networks.
• miRNAs impact diverse cellular functions in type
2 immune cells.
8 Archives of Immunology and Allergy V2 . I2 . 2019
• miRNAs provide novel biomarkers and therapeutic
strategies.
• lncRNAs also regulate allergic inflammation.
• lncRNAs act coordinately to decrease ASCMs
proliferation.
• lncRNAs thus provide novel therapeutic
strategies.
Ultra-low doses of molecules are capable of having an
effective regulatory effect on the cellular structures
involved in allergic diseases, especially asthma.It is
therefore possible to treat a chronic and sometimes
very unpleasant disease such as asthma over the long-
term without having to fear any adverse effects.
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Citation: Glady Gilbert. The Interplay between MiRNAs and LncRNAs in the Pathogenesis of Asthmatic
Diseases. Archives of Immunology and Allergy. 2019; 2(2): 01-09.
Copyright: © 2019 Glady Gilbert. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.

Archives of Immunology and Allergy V2 . I2 . 2019 9

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